Dose Intensity Research Articles

Postoperative chemotherapy relative dose intensity and overall survival in patients with colon cancer.

Quantifying the association of chemotherapy relative dose intensity (RDI) with overall survival may enable supportive care interventions that improve chemotherapy RDI to estimate their magnitude of potential clinical benefit. This cohort study included 533 patients with stage II-III colon cancer who initiated a planned regimen of 12 cycles of 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX) chemotherapy. The primary exposure was chemotherapy RDI. The primary outcome was overall survival. Restricted cubic splines estimated hazard ratios (HR). Chemotherapy regimen RDI was associated with overall survival in an L-shaped pattern (linear P = 0.006; nonlinear P = 0.057); the risk of death was flat above 85% but increased linearly below 85%. For example, a decrease in RDI from 85 to 75% was associated with an increased risk of death [HR: 1.20 (95% CI: 1.08, 1.52)], whereas an increase in RDI from 85 to 95% was not associated with the risk of death [HR: 1.06 (95% CI: 0.82, 1.38)]. If chemotherapy RDI is considered a potential surrogate of overall survival, supportive care interventions that improve chemotherapy RDI might confer a potential clinical benefit in this population.

Abstract 4562: Activity of PARP1-selective inhibitor SNV-001 in models of HRD cancers as monotherapy and in combination

Abstract Current FDA approved poly (ADP-ribose) polymerase inhibitors (PARPi) inhibit both PARP1 and PARP2. Genetic studies indicate that loss of PARP1 is synthetic lethal with homologous recombination deficiency (HRD), including BRCA1/2 mutations, and PARP2 depletion may be linked to hematologic toxicity. To date, no first generation PARPi has been successfully combined with standard of care (SoC) agents in the clinic without significant reduction in dosing intensity because of overlapping toxicities. A selective inhibitor could potentially improve the therapeutic index and provide additional opportunities in combination strategies especially with drugs that are prone to myelosuppression. SNV-001 potently and selectively inhibits PARP1 in biochemical and cellular assays. SNV-001 inhibits PARylation in the low nanomolar range with over 500-fold selectivity against PARP2. SNV-001 did not inhibit any other PARP family member tested up to 10 uM in biochemical assays confirming its selectivity for PARP1. In human erythroid and myeloid colony formation assays, the IC50s of SNV-001 for both lineages were approximately 100-times higher than the target efficacious concentration based on the IC95 for inhibition of DLD1 (BRCA2 -/-) colony formation. In a subcutaneous MDA-MB-436 (BRCA1mut) xenograft model, oral administration of SNV-001 once daily resulted in a dose-dependent tumor regression. SNV-001 showed greater efficacy at lower doses compared to olaparib at 100 mg/kg or at equivalent doses of AZD9574. SNV-001 showed promising synergy with SoC chemotherapies or DDR inhibitors in cell proliferation assays. SNV-001 enhanced cytotoxicity of the DNA-damaging agent topotecan or carboplatin in Capan-1 (BRCA2mut) and HCC1395 (BRCA1mut) cells. Synergy was seen between SNV-001 and cell cycle check point inhibitors camonsertib (ATRi) or adavosertib (WEE1i) in DLD1 (BRCA2 -/-) and UWB1.289 (BRCA1mut) cells, as DNA damage induced by PARP1 trapping relies on cell cycle modulation for repair. Combination of SNV-001 with polymerase theta inhibitor ART558 or USP1 inhibitor KSQ4279 exhibited synergistic effects in DLD1 (BRCA2 -/-) or UWB1.289 (BRCA1mut) cells. These results suggest that inhibition of microhomology-mediated end-joining and translesion synthesis pathways may further exacerbate SNV-001-induced DDR in certain cellular contexts.In summary, the PARP1 selective inhibitor SNV-001 demonstrates potent antitumor activity and shows promising synergy between SoC chemotherapies or DDR inhibitors. Current data highlight a potential strategy for improving treatment efficacy and overcoming resistance. Further clinical investigations are warranted to validate this combination strategy. Citation Format: Zhentian Li, Qipeng Fan, Mingming Gao, Jun Pan, Liangxing Wu, Wenqing Yao, Phillip C. Liu. Activity of PARP1-selective inhibitor SNV-001 in models of HRD cancers as monotherapy and in combination [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4562.

UV/TiO2 photocatalysis as post-treatment of anaerobic membrane bioreactor effluent for reuse

Advanced oxidation processes have been widely applied as a post-treatment solution to remove residual organic compounds in water reuse schemes. However, UV/TiO2 photocatalysis, which provides a sustainable option with no continuous chemical addition, has very rarely been studied to treat anaerobically treated effluents. In the current study, the removal of organics and nutrients from an anaerobic membrane bioreactor (AnMBR) effluent is evaluated during adsorption and photocatalysis processes under various conditions of TiO2 dose and UV intensity and compared to the effluent from an aerobic membrane bioreactor (AeMBR). The sequence for preferential adsorption on TiO2 was found to be phosphorus, inorganic carbon and then ammonia/organic carbon were found. The competing effect between the organics and nutrients, along with the low UV transmission efficiency caused by the need for high doses of TiO2, ultimately compromise the organic removal efficiency in the AnMBR permeate. TiO2 dosage was found to have a greater impact than UV intensity on improving the overall removal performance as nutrients are competing for the adsorption site but are not photodegraded. Under the same operational condition, the UV/TiO2 photocatalysis displayed a higher removal efficiency of organic matter and phosphorus in the AeMBR effluent due to a lower initial organics concentration and absence of ammonia as compared to the AnMBR effluent.

Association between albumin–bilirubin grade and plasma trough concentrations of regorafenib and its metabolites M-2 and M-5 at steady-state in Japanese patients

SummaryThe aim of the present study was to determine whether the trough plasma concentrations (C0) of regorafenib and its metabolites, the N-oxide metabolite (M-2) and the desmethyl N-oxide metabolite (M-5), in 21 patients receiving regorafenib therapy were affected by albumin-bilirubin (ALBI) grade. Regorafenib was administered at dosages ranging from 40 to 160 mg once daily on a 3-week-on, 1-week-off cycle. C0 values of regorafenib and its major metabolites were measured by high-performance liquid chromatography on day 8 after treatment initiation. The C0 values of regorafenib and metabolites M-2 and M-5 were significantly lower in patients with ALBI grade 2 as compared with grade 1 (P = 0.023, 0.003 and 0.017, respectively). The total C0 of regorafenib and its metabolites was significantly higher in ALBI grade 1 patients relative to grade 2 (3.489 μg/mL vs. 1.48 μg/mL; P = 0.009). The median relative dose intensity (RDI) of patients categorized as ALBI grade 2 was significantly lower than that of grade 1 patients (21.9% vs. 62.9%; P = 0.006). In 15 colorectal cancer patients among the total 21 patients, patients with ALBI grade 2 (n = 9) had a significantly shorter median overall survival time than patients with grade 1 (n = 6; P = 0.013). Administering a low dose of regorafenib to patients with ALBI grade 2 reduces the RDI of regorafenib and lowers treatment efficacy, as an appropriate C0 of regorafenib is not maintained. Monitoring the C0 of regorafenib regularly is necessary to guide dose adjustment.

Real-world use, dose intensity, and adherence to enfortumab vedotin in locally advanced or metastatic urothelial cancer

BackgroundEnfortumab vedotin (EV) monotherapy is approved for the treatment of advanced urothelial cancer as later-line therapy (post-immunotherapy and -platinum-chemotherapy) and as earlier-line therapy (cisplatin-ineligible, at least 1 prior therapy). We examined real-world EV monotherapy use, dose intensity and adherence across 280 US cancer clinics. MethodsThis postmarketing study used data from a nationwide (United States) deidentified patient-level electronic health record-derived database. Included were patients with advanced urothelial cancer initiating EV on or after December 19, 2019 (date of accelerated approval). We summarized characteristics of EV users using descriptive statistics and computed metrics of EV use, EV dose intensity, and EV treatment adherence. ResultsWe identified 416 advanced urothelial cancer patients initiating EV monotherapy. More than half of patients (55.3%) received EV as later-line therapy (3L+), and nearly half (44.7%) received EV as earlier line therapy (1 or 2L). Dosing frequency (mean [SD] 2.4 [0.5] treatments per 28 day cycle) and dose (1.1 [0.2] mg/kg) were lower than label indication guidelines (1.25 mg/kg, Day 1, 8, 15 of a 28 day cycle). Only 58.8% of patients received an average of >2 treatments per 28-day cycle. ConclusionsAmong patients with advanced urothelial cancer treated with EV monotherapy in contemporary practice, EV dosing frequency, and dosage was lower in clinical practice than recommended in the product labeling. Further research is required to understand clinical factors and outcomes associated with the differences observed.

The frequency of NUDT15 rs116855232 and its impact on mercaptopurine-induced toxicity in Syrian children with acute lymphoblastic leukemia.

Polymorphisms in NUDT15 may result in differences in mercaptopurine-induced toxicity. This study aimed to identify the frequency of the NUDT15 (c.415C>T; rs116855232) polymorphism and investigate the effect of this polymorphism on mercaptopurine-induced toxicity in a population of Syrian patients with childhood acute lymphoblastic leukemia (ALL). This is a retrospective study that included children with ALL reaching at least 6 months of maintenance therapy. The NUDT15 genotyping was determined using standard targeted sequencing of polymerase chain reaction products. The odds ratio (OR) for the association between toxicity and genotype was evaluated. A total of 92 patients were enrolled. The majority of the patients in the study population were low-risk (63.04%), followed by intermediate-risk (25%), and high-risk (11.96%). There were 5 patients (5.4%) with NUDT15 (c.415C>T; rs116855232) CT genotype, and 1 patient (1.08%) with NUDT15 TT genotype, with allele frequencies of C=0.962 and T=0.038. The mercaptopurine median dose intensity was 100%, 54.69%, and 5% for the genotypes CC, CT, and TT, respectively (P=0.009). Early onset leukopenia was significantly associated with the NUDT15 polymorphism (OR: 6.16, 95% CI: 1.11-34.18, P=0.037). There was no association between the NUDT15 genotype and hepatotoxicity. Approximately 6.5% of the study population exhibited reduced NUDT15 activity. The mercaptopurine dose intensity was considerably low in NUDT15 rs116855232 TT genotype compared with CT and CC. The dosage of mercaptopurine should be adjusted according to the NUDT15 genotype in pediatric patients with ALL.

Evaluation of Statin Indication and Dose Intensification Among Type 2 Diabetic Patients at a Tertiary Hospital.

Diabetes mellitus (DM) increases cardiovascular disease (CVD) incidence and mortality. While guidelines endorse statin use in type 2 DM (T2DM) to mitigate cardiovascular risks and mortality, challenges like statin initiation and prompt treatment adjustments affect patient outcomes. This study aimed to assess the appropriateness of indications for and dose intensification of statin therapy among T2DM patients at Tikur Anbessa Specialized Hospital (TASH). A hospital-based cross-sectional study was conducted from April 1 to June 30 2020. In total, 405 T2DM patients were selected using a systematic random sampling technique. The data were analyzed using SPSS version 26.0. An adjusted odds ratio (OR) was used and a 95% confidence interval (CI) and p-values of <0.05 were utilized to determine statistical significance. Of the total 405 participants, 346 (85.4%) started taking statins for primary or secondary prevention purposes. Indication for statin use was appropriate in 96.2% patients, while for 216 (62.4%) patients their doses were appropriately intensified. Predictors of the inappropriateness of statin use were an atherosclerotic cardiovascular disease (ASCVD) score of ≥7.5% (AOR=0.28; 95% CI: 0.102-0.738, p=0.01), the presence of dyslipidemia (AOR=4.48; 95% CI: 1.85-10.84; p=0.001), initiation of aspirin therapy (AOR=3.7; 95% CI: 1.522-9.144; p=0.004), and an LDL-cholesterol level of 70-189 mg/dL (AOR=0.124; 95% CI: 0.042-0.365; p=0.001). DM duration of ≥10 years (AOR=2.51; 95% CI: 1.35-4.66, p=0.004), male gender (AOR=2.04; 95% CI: 1.16-3.58, p=0.013), age ≥65 years (AOR=2.15; 95% CI: 1.23-3.75, p=0.007) and uncontrolled blood pressure (AOR=2.09; 95% CI: 1.07-4.08, p=0.031) were associated with inappropriate statin intensification. The study found that indication of statins was optimal and about two-thirds of patients had their doses appropriately intensified. Monitoring is needed to avoid inappropriate intensification of statin therapy, particularly in patients with longer diabetes duration, those of male gender and advanced age, and those with uncontrolled blood pressure.

Phenotype versus genotype to optimize cancer dosing in the clinical setting-focus on 5-fluorouracil and tyrosine kinase inhibitors.

Cancer medicines often have narrow therapeutic windows; toxicity can be severe and sometimes fatal, but inadequate dose intensity reduces efficacy and survival. Determining the optimal dose for each patient is difficult, with body-surface area used most commonly for chemotherapy and flat dosing for tyrosine kinase inhibitors, despite accumulating evidence of a wide range of exposures in individual patients with many receiving a suboptimal dose with these strategies. Therapeutic drug monitoring (measuring the drug concentration in a biological fluid, usually plasma) (TDM) is an accepted and well validated method to guide dose adjustments for individual patients to improve this. However, implementing TDM in routine care has been difficult outside a research context. The development of genotyping of various proteins involved in drug elimination and activity has gained prominence, with several but not all Guideline groups recommending dose reductions for particular variant genotypes. However, there is increasing concern that dosing recommendations are based on limited data sets and may lead to unnecessary underdosing and increased cancer mortality. This Review discusses the evidence surrounding genotyping and TDM to guide decisions around best practice.

Feasibility study of a multimodal prehabilitation programme in women receiving neoadjuvant therapy for breast cancer in a major cancer hospital: a protocol

IntroductionNeoadjuvant therapy has become a standard treatment for patients with stage II/III HER2 positive and triple negative breast cancer, and in well-selected patients with locally advanced and borderline resectable high...

Safety and Efficacy of Gemcitabine Plus Cisplatin Against Recurrent/Metastatic Nasopharyngeal Carcinoma: A Retrospective Study.

Although gemcitabine plus cisplatin (GC) prolongs survival in patients with recurrent or metastatic nasopharyngeal carcinoma (R/M NPC) compared with fluorouracil plus cisplatin, no study has evaluated the efficacy and safety of GC in nonendemic regions, including Japan, yet. Therefore, we assessed the safety and efficacy of GC in Japanese patients with R/M NPC. We retrospectively reviewed patients with R/M NPC who received GC treatment at the Aichi Cancer Center Hospital from January 2017 to March 2020. The main eligibility criteria were histologically confirmed NPC, Eastern Cooperative Oncology Group performance status (ECOG PS) of 0-2, and locally recurrent disease unsuitable for local treatment or metastatic disease. The regimen was administered every 3 weeks (gemcitabine, 1,000 mg/m2 on days 1 and 8; cisplatin, 80 mg/m2 on day 1). Fourteen patients (median age, 58 years) were included in the study. Two patients had an ECOG PS of 2 and 11 exhibited nonkeratinizing histology. Of the eight patients with measurable lesions, one exhibited complete response and seven exhibited partial response, with an objective response rate of 75%. Median progression-free survival and overall survival were 7.7 and 24.2 months, respectively. Common grade 3 or 4 adverse events included neutropenia (64%), thrombocytopenia (14%), and febrile neutropenia (14%). The median relative dose intensity of gemcitabine and cisplatin was 62% and 60%, respectively. No treatment-related deaths occurred. The GC regimen demonstrates promising activity and is tolerable in Japanese patients with R/M NPC.

The effect of the relative dose intensity of chemoradiotherapy on the effectiveness of therapy of locally advanced unresectable non-small cell lung cancer

The purpose of the study. To estimate the number of patients with the preservation of relative dose intensity (RDI) ≥ 80 % of first-line antitumor therapy in patients with unresectable non-small cell lung cancer (NSCLC), and to compare the effectiveness of therapy in groups with optimal and lower RDI.Patients and methods. The study included 30 patients (25 men and 5 women) with locally advanced unresectable NSCLC. The median age was 57 years. The main criterion for inclusion in the study was morphologically verified NSCLC with stage IIIB-IIIC of the disease. All patients underwent simultaneous chemoradiotherapy. According to the histogenesis of the tumor process, patients with a squamous cell variant prevailed.Results. The data obtained from 22 (73.3 %) patients who retained a relative dose intensity of RDI &gt; 80 % demonstrated that given dose intensity is sufficient to achieve a stable antitumor effect. In 8 (26.7 %) cases, however, the RDI was less than 80 %, which affected the effectiveness of the treatment. The median follow-up for overall survival (OS) was 29.2 months, progression-free survival (PFS) was 15.1 months, and local control was 21.9 months. in all patients included in the analysis. The indicators of OS in the second year had an advantage in the group of patients with RDI &lt; 80 % and amounted to 73.3 % compared with 60.5 % in patients with RDI &gt; 80 %. PFS was higher in the group of patients with high dose intensity, in the first year of follow-up it was 75.6 % compared with the group of patients with RDI &lt; 80 % (62.5 %), in the second year of follow-up, PFS was 27.2 % and 20.8 %, respectively. Local control was 90.2 % in the first year in the group of patients with RDI &gt; 80 % and 62.5 % in the group of patients with RDI &lt; 80 %. The second year of follow-up demonstrated the advantage of the group of patients with RDI &gt;80 % in terms of local control and amounted to 48.1 % versus 34.7 %, respectively.Conclusion. The results obtained show that maintaining relative dose intensity at a high level has a positive effect on survival rates and local control of patients with locally advanced unresectable NSCLC. However, there is a cohort of patients who did not receive the planned amount of treatment, due to the high toxicity of simultaneous chemoradiotherapy. It is necessary to develop new approaches to concomitant therapy aimed at reducing the toxicity of the combined treatment and achieving maximum antitumor effect.

Multicenter randomized phase II study on S-1 and oxaliplatin therapy as an adjuvant after hepatectomy for colorectal liver metastases (YCOG1001).

The high recurrence rate of colorectal cancer liver metastasis (CRCLM) after surgery remains a crucial problem. However, adjuvant chemotherapy after hepatectomy for CRCLM has not yet been established. This study evaluated the efficacy of adjuvant therapy with S-1 and oxaliplatin (SOX). In a multicenter, randomized, phase II study, patients undergoing curative resection of CRCLM were randomly enrolled in a 1:1 ratio to either the low- or high-dose group. S-1 and oxaliplatin were administered from days 1 to 14 of a 3-week cycle as a 2-h infusion every 3weeks. The dose of S-1 was fixed at 80mg/m2. The doses in the low- and high-dose oxaliplatin groups were 100mg/m2 (low-dose group) and 130mg/m2 (high-dose group), respectively. This treatment was repeated eight times. The primary endpoint was the rate of discontinuation owing to toxicity. The secondary endpoints were the relapse-free survival (RFS) and frequency of adverse events (AEs). Between August 2010 and March 2015, 44 patients (low-dose group: 31 patients and high-dose group: 13 patients) were enrolled in the study. Of these, one patient was excluded from the efficacy analysis. In the high-dose group, five of nine patients were unable to continue the study due to toxicity in February 2013. At that time, recruitment to the high-dose group was stopped from the protocol. The relative dose intensity (RDI) for S-1 in the low- and high-dose groups were 49.8 and 48.7% (p = 0.712), and that for oxaliplatin was 75.9 and 73.0% (p = 0.528), respectively. The rates of discontinuation due to toxicity were 60 and 53.8% in the low- and high-dose groups, respectively, with no marked difference noted between the groups (p = 0.747). The frequency of grade ≥ 3 common adverse events was neutropenia (23.3%/23.1%), diarrhea (13.3%/15.4%), and peripheral sensory neuropathy (6.7%/7.7%). The disease-free survival (DFS) at 3years was 52.9% in the low-dose group, which was not significantly different from that in the high-dose group (46.2%; p = 0.705). SOX regimens as adjuvant therapy after hepatectomy for CRCLM had high rates of discontinuation due to toxicity in both groups. In particular, the RDI of S-1 was < 50%. Therefore, the SOX regimen is not recommended as adjuvant chemotherapy after hepatectomy for CRCLM.

Quantifying Chemotherapy Delivery in Older and Younger Women With Early-Stage Breast Cancer Using Longitudinal Cumulative Dose.

Delivery of cancer treatments, such as chemotherapy, requires a complex set of decisions that can change over time. Traditional measures of chemotherapy delivery, such as relative dose intensity, measure the amount of chemotherapy received by the end of treatment but mask the timing of dose reductions, delays, and discontinuation. These events may be important for delivering timely interventions to support adherence and lower the risk of recurrence. We used an institutional database to identify women diagnosed with stage I-III breast cancer receiving adjuvant chemotherapy with a standard 4-cycle regimen of docetaxel + cyclophosphamide (TC, every 21 days) from April 2014 to December 2019. LCD was calculated as the amount of a given chemotherapy agent delivered at a specified time, t, divided by the total planned standard chemotherapy dose at time t. We visualized LCD curves for each chemotherapy agent and reported the median LCD and interquartile range (IQR) at the end of the regimen, overall and by age group (<65 years vs. 65+ years). The study population included 80 women. At the end of treatment, overall median LCDs for both cyclophosphamide and docetaxel were 100% (IQR: 99.6%, 100%), suggesting that TC was well tolerated. However, the lower quartile LCD for cyclophosphamide was 98.7% in older women treated with TC compared with 99.7% in younger women. Within our cohort, adjuvant TC was well tolerated with LCD curves showing largely on-time and full-dose administration. Subgroup analyses showed only slight decreases in adjuvant TC LCD for patients aged 65+ versus <65 years.

Effect of erythropoietin-stimulating agent use on belzutifan antitumor activity in patients with VHL disease–associated renal cell carcinoma: Post hoc analysis of the LITESPARK-004 study.

3 Background: The ongoing, open-label, phase 2 LITESPARK-004 study (NCT03401788) showed that belzutifan, a HIF-2α inhibitor, exhibited antitumor activity in patients (pts) with VHL disease associated renal cell carcinoma (RCC), pancreatic neuroendocrine tumors (pNETs), and CNS hemangioblastomas. The most common adverse event (AE) of any grade was anemia and pts could have received erythropoietin-stimulating agents (ESA) and/or blood transfusions for management. This exploratory post-hoc analysis described pattern of ESA use and whether use of ESA impacted antitumor activity to belzutifan in pts with VHL disease. Methods: Pts (≥18 years) with germline VHL alterations, ≥1 measurable nonmetastatic RCC tumor, no tumor of &gt;3 cm requiring immediate surgery, and no prior anticancer systemic treatment received oral belzutifan 120 mg once daily until disease progression, unacceptable toxicity, or pt withdrawal. End points included objective response rate (ORR) and duration of response (DOR) in VHL disease–associated RCC and non-RCC neoplasms per RECIST v1.1 by independent central review, and safety. Efficacy and safety outcomes among pts who received and did not receive ESA were evaluated. Data cutoff was April 1, 2022. Results: Of 61 treated pts, 14 (23%) received ESA and 47 (77%) did not. Median (range) time to onset of ESA use was 151 days (59-886) and median dose per pt was 5 injections (range 1-35). Duration of belzutifan exposure for ≥12 months was achieved in 100% of pts who received ESA vs 92% in pts who did not receive ESA. Median (range) relative dose intensity was 97.4 (51.4-100) and 98.8 (26.4-100) for pts who received and did not receive ESA, respectively. ORR for VHL-associated RCC was 71% (10/14, 95% CI, 42-92) for pts who received ESA and 62% (29/47, 46-76) for those who did not. Median DOR was not reached (NR) for pts who received and who did not receive ESA (NR, range 5.5+ to 33.5+ months and NR, range 5.4+ to 35.8+ months). All pts in both groups had a response for ≥12 months. In pts with CNS hemangioblastomas, ORR was 46% (5/11, 17-77) for pts who received ESA and 44% (17/39, 28-60) for those who did not. In pts with pNETs, ORR was 100% (4/4, 40-100) for pts who received ESA and 89% (16/18, 65-99) for those who did not. Median DOR was not reached for both groups in pts with CNS hemangioblastomas and pNETs. Among pts who received and did not receive ESA, 5 (36%) and 6 (13%) pts had at least 1 dose reduction, respectively. All pts reported at least 1 AE but a larger percentage of pts who received ESA had AEs of grade 3 or higher than those who did not receive ESA (57% and 40%). Conclusions: In this exploratory, post-hoc analysis of LITESPARK-004, data suggests that administration of ESA did not adversely impact overall drug exposure or efficacy of belzutifan in pts with VHL disease associated RCC, CNS hemangioblastomas, and pNETs. Clinical trial information: NCT03401788 .

Geriatric risk model for older patients with diffuse large B-cell lymphoma (GERIAD): a prospective multicenter cohort study.

Optimal risk stratification based on simplified geriatric assessment to predict treatment-related toxicity and survival needs to be clarified in older patients with diffuse large B-cell lymphoma (DLBCL). This multicenter prospective cohort study enrolled newly diagnosed patients with DLBCL (≥ 65 yr) between September 2015 and April 2018. A simplified geriatric assessment was performed at baseline using Activities of Daily Living (ADL), Instrumental ADL (IADL), and Charlson's Comorbidity Index (CCI). The primary endpoint was event-free survival (EFS). The study included 249 patients, the median age was 74 years (range, 65-88), and 125 (50.2%) were female. In multivariable Cox analysis, ADL, IADL, CCI, and age were independent factors for EFS; an integrated geriatric score was derived and the patients stratified into three geriatric categories: fit (n = 162, 65.1%), intermediate-fit (n = 25, 10.0%), and frail (n = 62, 24.9%). The established geriatric model was significantly associated with EFS (fit vs. intermediate-fit, HR 2.61, p < 0.001; fit vs. frail, HR 4.61, p < 0.001) and outperformed each covariate alone or in combination. In 87 intermediate-fit or frail patients, the relative doxorubicin dose intensity (RDDI) ≥ 62.4% was significantly associated with worse EFS (HR, 2.15, 95% CI 1.30-3.53, p = 0.002). It was related with a higher incidence of grade ≥ 3 symptomatic non-hematologic toxicities (63.2% vs. 27.8%, p < 0.001) and earlier treatment discontinuation (34.5% vs. 8.0%, p < 0.001) in patients with RDDI ≥ 62.4% than in those with RDDI < 62.4%. This model integrating simplified geriatric assessment can risk-stratify older patients with DLBCL and identify those who are highly vulnerable to standard dose-intensity chemoimmunotherapy.

P684 Using a pharmacokinetic simulation model to determine the optimal infliximab intensification strategy to address loss of response in inflammatory bowel disease

Abstract Background The optimal dose intensification strategy to address loss of response associated with low infliximab levels remains uncertain. Favorable associations between higher infliximab levels and objective endpoints imply that post-intensification trough and treatment targets may have utility. This simulation study aimed to identify intensification strategies capable of achieving post-intensification trough thresholds associated with aspirational treatment targets in Crohn’s disease (CD) and ulcerative colitis (UC). Methods A previously published infliximab pharmacokinetic model, applied to 200 simulated patients, identified those with subtherapeutic(&amp;lt;3.00mg/L) trough levels after 30-weeks of standard dosing, and subsequently applied ten dose intensification strategies (Figure 1) over a further 32 weeks. The proportion of simulations achieving infliximab trough thresholds associated with endoscopic remission (CD &amp;gt;9.7mg/L; UC &amp;gt;7.5mg/L) was the primary outcome, with clinical improvement (CD &amp;gt;7.0mg/L; UC &amp;gt;3.7mg/L) and perianal fistula healing (CD &amp;gt;10.1mg/L) representing secondary outcomes. Outcomes were stratified by intensity of dose intensification, with five deemed intensive (&amp;gt;10mg/kg 8-weekly). The impact of pre-intensification antibodies to infliximab (ATI) on post-intensification trough levels was also evaluated. Results The median pre-intensification infliximab trough level was 0.91mg/L (IQR 1.31). Intensive intensification strategies were more likely to achieve infliximab trough concentrations associated with endoscopic remission (UC: 34.76 v 10.56%, CD: 25.80 v 4.92%), clinical improvement (UC: 61.40 v 34.52%, CD: 39.58 v 12.12%) and perianal fistula healing (24.70 v 4.50%, all p&amp;lt;0.01) than standard intensification strategies (Figure 2). When controlling for cumulative (mg/kg) infliximab dose over 32 weeks, strategies that concurrently dose increased and interval shortened achieved the highest trough levels (all p&amp;lt;0.01). Patients simulated to have ATI prior to dose intensification had lower median infliximab trough levels at weeks 30/32 (3.38 mg/L, IQR 5.52 mg/L) compared to those without ATI (3.89 mg/L IQR 6.14 mg/L) across all dose intensification strategies (p=0.015). Conclusion This simulation-based analysis highlights the potential of using post-intensification trough level targets to guide dosing strategy and intensity. Combined high-dose, interval-shortened strategies appear to achieve higher infliximab levels, which may be important in the pursuit of stringent endpoints such as endoscopic remission and fistula healing. These findings require validation across real-world cohorts.

P569 Persistence and safety of upadacitinib in Crohn’s disease and ulcerative colitis in real life: results from a Spanish nationwide study

Abstract Background Upadacitinib (UPA) has demonstrated its efficacy in patients with inflammatory bowel disease (IBD) in clinical trials. However, these results may differ from those achieved in clinical practice. Thus, persistence and safety should be analysed in a real-world scenario. Main aim: to evaluate the persistence of UPA in real life, both in Crohn’s disease (CD) and ulcerative colitis (UC). Secondary aims: to assess the effectiveness and safety of UPA. Methods Multicentre, retrospective study of IBD patients who received UPA for IBD in clinical practice. Persistence was calculated from the date of the first dose to the date of the last dose of UPA. For effectiveness assessment, only patients with active IBD at baseline were considered. Active disease was defined as Harvey-Bradshaw index &amp;gt;4 in CD, and partial Mayo score &amp;gt;2 in UC. Negative imputation method was used to deal with missing data. Cox regression and logistic regression analyses were used to identify predictive factors of treatment persistence and effectiveness, respectively. Results One hundred patients from 34 centres were included, 68 with CD and 32 with UC. All patients had been previously exposed to biologics (median 4, IQR 3-4), and 26% to JAK inhibitors (78% in UC); 37% of them were on steroids at baseline. Regarding UPA survival, 81% of patients remained on UPA at month 6, and 66% at month 12 (figure 1). Loss of response was observed in 34% per patient-year of follow-up. Dose intensification was required in 18%, 72% of whom responded clinically. Finally, 23 patients interrupted UPA during the follow-up. Age below 40 at UPA start and CD were associated with higher risk of UPA withdrawal (HR 2.4; 95%CI:1.0-5.7 and HR 3.7; 95%CI:1.0-12.9, respectively). Seventy-eight patients had active disease at baseline and were considered for the effectiveness analysis. Short-term clinical remission was achieved in 51%, 59% and 64% at week 4, 8 and 12; focusing on the type of IBD, clinical remission was achieved in 79% of UC vs. 54% of CD (p=0.03) at week 12. In the long-term, 53% and 42% remained in clinical remission at months 6 and 12. Clinical remission in patients exposed to JAK inhibitors was achieved in 75% and 79% at week 8 and 12, respectively; and in the long-term, in 54% and 55% at months 6 and 12. A total of 41 patients (41%) presented at least one adverse event (Table 1). Conclusion In the largest real-life cohort of IBD patients treated with UPA, the proportion of patients maintaining UPA at 12 months seems relatively high, regardless of prior exposure to JAK inhibitors. UPA seems to be effective in inducing and maintaining clinical remission, both in CD and in UC. The safety profile was similar to that previously described.

P916 Off-label dose escalation of Ustekinumab in Inflammatory Bowel Disease patients. Incidence rate, timing, dosing patterns and outcomes

Abstract Background In patients with inflammatory bowel disease (IBD), after intravenous induction,Ustekinumab (UST) is administered as maintenance 90 mg every 8 (Q8) or 12 weeks (Q12) subcutaneously. As with other biological drugs, dose intensification may be effective after inadequate response or loss of response. However, different dosing regimens have been used and the best strategy is unknown. Our aim was to evaluate the incidence and efficacy of UST off-label dose escalation in IBD. Methods We performed an observational cohort study in 2 hospitals in Vigo,Spain. All patients who started UST between 1 June 2017 and 31 December 2022 to control their active IBD were enrolled. The primary endpoints were incidence rate and outcomes of UST off-label dose intensification. Secondary endpoints were the timing of dose escalation and the patterns indicated. Results 1 173 IBD patients received UST: females 53.8% (93), mean age 49.7(15.5) years, Crohn´s disease 82% (142), previous anti-TNF 93.6% (162) and vedolizumab 22.5% (39) (Table 1). Subcutaneous UST was maintained Q8 in 63.6% (110) and Q12 in 34.7% (60). Baseline activity data were higher in Q8 patients (p=0.001). At 16 week 23 patients (13.3%) had no response, but 9 (39.1%) became late responders at 6 months. Of the 173 IBD patients included, 38.2% and 30.6 % achieved clinical response and clinical remission at 1 year. Dose escalation was performed in 32.4% (56) with different patterns: 54.5% Q4 (30), 21.8% reinduction plus Q4 (12), 12.7% Q6 (7) and 10.9% only intravenous reinduction (6). The timing of dose escalation was: before 6 months in 19.6% (11), at 12 months 42.8% (24) and at 2 years 73.2% (41). Response and remission were achieved in 28.6% (16) and 41.1% (23) after dose escalation respectively. In 6.4% of the patients (11) a second dose escalation was indicated. Neither previous anti-TNF or vedolizumab nor concomitant use of steroids at starting UST were associated to dose escalation. IBD patients that were initially scheduled to receive subcutaneous UST Q12 needed less dosing escalation (p&amp;lt;0.001). Conclusion Off-label UST dose escalation was frequent and effective in achieving response in IBD patients. The schemes of dose-escalation were heterogeneous between the participants. Patients initially scheduled Q12 due to lower inflammatory activity required less dose escalation.

P1068 Limited long-term efficacy of corticosteroids in microscopic colitis emphasizing the need for advanced therapies

Abstract Background Microscopic colitis (MC) is a chronic inflammatory bowel disease, characterized by chronic watery diarrhea, and consisting of 2 subtypes: collagenous (CC) and lymphocytic (LC) colitis. It mainly affects middle-aged adults, although it can occur at any age. The only approved therapy is budesonide, preferably administered in a tapering regimen given the high relapse rates. However, little is known about the long-term natural history of the disease. Methods All adult patients diagnosed with MC after clinical and histological assessment at our referral center between 2014 and 2022 were reviewed. Patients with follow-up less than 3 months or in whom no clear description of initiated therapy could be identified by retrospective chart review, were excluded for evaluation of long-term outcomes. Clinical remission was defined according to the Hjortswang criteria as &amp;lt; 3 stools/day or &amp;lt; 1 watery stool/day. Data on relapse rates, subsequent therapies and surgery were collected. Results Three-hundred twenty-four patients were included, of whom 198 (CC 38.3%, LC 61.7%) were eligible for long-term assessment (Table 1) with a median follow-up of 3.7 [1.1 – 6.3] years. Median age at diagnosis was 63.4 [51.6-74.7] years. Concomitant diseases occurring in 3% or more included thyroid dysfunction (11.6%), coeliac disease (3.5%) and Parkinson’s disease (5.1%), which numerically was more prevalent in the LC (7.4%) than CC (1.3%) population (p=0.09). A minority of patients had a family predisposition of IBD (5.6%). Spontaneous clinical remission occurred in 37 (18.6%) patients, while 4 (2.0%) patients were treated with 5ASA. Most patients (79.3%) were treated with corticosteroids, resulting in 81.1% clinical remission within 3 months. Eighty-six patients (54.8%) flared upon steroid tapering and/or withdrawal requiring corticotherapy reinitiation, prolongation or dose intensification. Due to steroid resistance or dependency, subsequent treatment options included 5ASA (n=14), cholestyramine (n=11), methotrexate (n=6) and azathioprine (n=8), all with limited effect. More advanced therapies are being used, including anti-TNF agents (n=25), vedolizumab (n=9) and JAK inhibitors (n=8). Eighteen patients (9.2%) are currently on maintenance advanced therapies for MC. Two treatment-refractory patients underwent colectomy. Conclusion In this large single-center retrospective analysis, steroids confirmed their first line position to induce clinical remission in MC. However, more than 50% of patients relapsed upon steroid tapering and/or withdrawal, resulting in a substantial need for advanced therapy in this patient population. The long-term efficacy and safety of these advanced IBD therapies in MC should therefore be further investigated.

P1081 Pharmacokinetics and immunogenicity of the ustekinumab biosimilar candidate ABP 654 in patients with moderate-to-severe plaque psoriasis

Abstract Background ABP 654 is being developed as a biosimilar candidate to ustekinumab reference product (RP), a biologic agent used in the treatment of certain chronic, immune-mediated, inflammatory diseases. Previously, we reported no clinically meaningful differences in efficacy or safety between ABP 654 and ustekinumab RP in a 52-week randomised, double-blinded, active-controlled study in patients with moderate-to-severe plaque psoriasis. Here, we describe the pharmacokinetics (PK) and anti-drug antibody (ADA) results from the same study. Methods A total of 563 patients were randomised in a 1:1 ratio to receive ABP 654 or ustekinumab RP at a subcutaneous dose of 45 mg (baseline body weight [BW] ≤ 100 kg) or 90 mg (baseline BW &amp;gt; 100 kg) (Fig. 1). Serum samples for PK and ADA evaluations were collected at various timepoints. Concentrations of ABP 654 and ustekinumab RP were measured using an electrochemiluminescent (ECL) assay based on the Meso Scale Discovery platform. All ADA samples were tested in a validated binding, acid-dissociation ECL assay. Samples testing positive for binding antibodies were evaluated for neutralising ADA in a validated ECL-based affinity capture elution assay. Results From baseline to Week 52, the geometric least-squares (LS) means of trough serum concentrations were similar between the ABP 654 and ustekinumab RP groups. In addition, the geometric LS means of serum concentrations were similar post Week 28 for patients (ABP 654, n=25 and ustekinumab RP, n=34) who received dose intensification. Of patients with a post-baseline ADA result through Week 28, 52 (18.6%) patients in the ABP 654 group and 104 (37.1%) patients in the ustekinumab RP group tested positive for binding ADAs. Of these, 24 (8.6%) patients in the ABP 654 group and 50 (17.9%) patients in the ustekinumab RP group tested positive for neutralising ADAs. For dose intensification patients with a post-baseline result post Week 28, no patients in the ABP 654 group tested positive for binding or neutralising ADAs, and 2 (5.9%) patients in the ustekinumab RP group tested positive for binding and neutralising ADAs. Conclusion Throughout the study, serum trough concentrations remained comparable between ABP 654 and ustekinumab RP. While the percentages of binding and neutralising ADAs were numerically lower for the ABP 654 group compared with the ustekinumab RP group through Week 28 (and in patients who received dose intensification), the available clinical efficacy, safety, and PK data suggest that these differences were not clinically impactful. Overall, the results support a conclusion of no clinically meaningful differences between ABP 654 and ustekinumab RP.